JPH1067728A - Fluorine-containing sugar derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound useful as a MRI contrast medium by modifying only many magnetically equivalent fluorine atoms giving the same signal to introduce groups having tissue selectivity and improving the background. SOLUTION: A fluorine-containing sugar derivative of the formula: R<c> NHR<f> (R<c> is a sugar chain alkyl residue; R<f> is the residue of a compound containing one to several magnetically equivalent trifluoromethyl groups), e.g. a sugar amide of formula I. The compound of formula I is produced by reacting a sugar lactone of formula II [(n) is 0-4] with a new fluorinated amino compound of the formula: NR<f> in the presence of a proper catalyst such as NaCN in a proper solvent such as an alcoholic solvent (e.g. methanol) or an aprotic polar solvent (e.g. dimethylformamide) at -50 to 200 deg.C, preferably room temperature to 150 deg.C, for 10min to 120hr, preferably 1 to 10hr.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel fluorine-containing sugar derivative useful as a contrast agent for MRI (magnetic resonance imaging), a method for producing the same, and an intermediate for producing the same. In detail, M
A compound in which a structure that gives a strong singlet ¹⁹ F signal in RI is linked to a sugar chain having tissue selectivity,
The present invention relates to a production method and an intermediate for the production.

[0002]

2. Description of the Related Art
I is an excellent method for accurately diagnosing a disease by visually imaging a pathological morphological change of a living body, and is one of the diagnostic methods widely used. MRI currently used in clinical practice uses ¹ H of water as a nucleus for detection, and water molecules in the living body vary in different environments depending on the tissue in which it exists or whether there is a pathological abnormality in the tissue. The difference in relaxation time of the ¹ H nucleus caused by being placed in the image is imaged. In this case, by affecting to ¹ H nuclear relaxation time, manifestation of environmental differences, or for the purpose of achieving the sharpening of the image, but MRI contrast agents are often used, both of ¹ H nuclei of water molecules It is still used for MRI diagnosis as a detected nuclide.

On the other hand, instead of measuring water molecules in a living body, an MRI diagnosis using a nuclide other than ¹ H that can be detected by NMR (nuclear magnetic resonance) spectroscopy as a measurement nuclide has been attempted. For example, ¹⁹ F, ²³ Na, ³¹ P, and ¹³ C are used as detection nuclei. By using nuclides that are not present in living tissue, MRI diagnosis using ¹ H as a nuclide cannot be performed, and image diagnosis using a detected nucleus as a tracer can be performed, or chemical shift that cannot be obtained with MRI diagnosis using ¹ H as a nuclide. The information about is obtained. Therefore, the usefulness of MRI diagnosis using nuclides other than ¹ H as measurement nuclides is extremely high.

Fluorine ( ¹⁹ F) is a stable nuclide that can be detected by NMR spectroscopy. 1) The detection sensitivity is as high as 83% of ¹ H, and 2) the natural abundance is 1
00% of the low-cost elements, also 3) MR for general of the ¹ H
It has features that are advantageous as nuclides for MRI diagnosis, such as being measurable with an I diagnostic device. For this reason, attempts to apply MRI diagnosis using ¹⁹ F as a detection nucleus to clinical use have been particularly actively performed (Biochem.
264 , 829-835 (1989), Glycoco
njugate J .; , 5 , 145-50 (198
8), JP-A-2-270832, JP-A-7-97340, etc.). However, clinically still acceptable ¹⁹ FM
There is no RI contrast agent. The reason may be that the detection sensitivity of the ¹⁹ F-MRI contrast agent that has been attempted in the past was not sufficiently high. On the other hand, as a method for increasing the detection sensitivity as a contrast agent, administration of a large amount of a contrast agent can be considered, but this method is not generally accepted in terms of safety.

[0005]

SUMMARY OF THE INVENTION It is an object of the present invention gives a strong single singlet ¹⁹ F signal strength, a feature also of increasing only the concentration of the target tissue to improve the contrast between the background Have, MR
An object of the present invention is to provide a ¹⁹ F-MRI contrast agent that can be used for clinical application to I diagnosis.

[0006]

The present inventors have SUMMARY OF THE INVENTION As a result of intensive investigations to achieve the objects described above, to give a strong single singlet ¹⁹ F signal intensity is a number that gives the same signal By modifying only the magnetically equivalent fluorine atom of the above, and in order to increase only the concentration in the target tissue in order to improve the contrast with the background, by introducing a group having tissue selectivity, They have found for the first time that the object can be achieved, and have completed the present invention. That is, the gist of the present invention is the following formula (I)

[0007]

Embedded image R ^c NHR ^f (I)

(Wherein, R ^c represents a sugar acyl residue having tissue selectivity, and R ^f represents one or more magnetically equivalent trifluoromethyl groups bonded to a carbon atom to which no hydrogen atom is bonded.) , A fluorine-containing sugar derivative represented by the following formula (I), a medicament for internal diagnosis containing the compound as an essential component, and the following (I) useful as a synthetic intermediate of the compound:
X) expression

[0009]

^{Embedded image} H ₂ NR ^f1

Where R ^f1 is

[0011]

_Embedded image-(CH ₂ ) _k AR _m , —CH _p (CH ₂ O
R) _3-p or _{- (CH 2) k CH q} (CONHR 1)
_3-q

(Where k represents an integer of 1 to 5, and m represents 1
Or 2 is represented. R is

[0013]

Embedded image

Where A is

[0015]

Embedded image —CONH—, —NH—, —NHCO—, —
NHSO _2- , -O-, -S-, -N- or -CON
−

Represents the following. However, when m represents 1, A is

[0017]

-CONH-, -NH-, -NHCO-,-
NHSO _2- , -O- or -S-

When m represents 2, A is

[0019]

[Image Omitted] -N- or -CON-

Represents the following. Also R

[0021]

Embedded image —C (CF ₃ ) ₃

In the expression, A is

[0023]

Embedded image

Represents p represents 0 or 1, and q represents 0 or 1. R ¹ is

[0025]

Embedded image

## EQU1 ## ). A fluorinated amino compound represented by the formula (X):

[0027]

Embedded image

(Wherein R ^f1 has the same meaning as described above), and a compound represented by the following formula (XI):

[0029]

Embedded image

(Wherein n has the same meaning as described above), and the sugar lactone compound represented by the following formula (XII)

[0031]

Embedded image H ₂ NR ^f (XII)

Wherein R ^f is the same as defined above, wherein the compound is reacted with a fluorinated amino compound represented by the following formula (XIII):

[0033]

Embedded image

(Wherein n and R ^f have the same meanings as described above). Hereinafter, the present invention will be described in detail.

[0035]

BEST MODE FOR CARRYING OUT THE INVENTION In the above definition, the “tissue-selective sugar chain acyl residue” defined by R ^c is defined as an affinity for an asialoglycoprotein receptor present in organs and cells in a living body. The acyl residue is not particularly limited as long as it is an acyl residue of a monosaccharide or polysaccharide having a property, but a sugar compound acyl residue represented by the following formula (II) is preferable from the viewpoint of the content of a fluorine atom in one molecule.

[0036]

Embedded image

(In the formula, n represents an integer of 0 to 4.) In the present invention, it may be an acyl residue of a monosaccharide or a disaccharide represented by the following formula (III) or (IV). Preferably

[0038]

Embedded image

Specific examples thereof include D-galactonic acid,
Acyl residues of monosaccharide acids such as D-gluconic acid and D-mannonic acid, [O-β-D-galactopyranosyl- (1 → 4)]
-D-gluconic acid (lactobionic acid), [O-β-D-
Glucopyranosyl- (1 → 4)]-D-gluconic acid,
[O-β-mannopyranosyl- (1 → 4)]-D-gluconic acid, [O-β-galactopyranosyl- (1 → 4)]
And acyl residues of disaccharide acids such as -D-galactonic acid. Particularly, in the present invention, [O-β-D-galactopyranosyl- (1 → 4)]-represented by the following formula (V):
D-gluconic acid residue,

[0040]

Embedded image

[O-β-D-glucopyranosyl- (1 → 4)]-D-gluconic acid residue represented by the following formula (VI):

[0042]

Embedded image

D-galactonic acid residue represented by the following formula (VII):

[0044]

Embedded image

Alternatively, it preferably represents a D-mannonic acid residue represented by the following formula (VIII).

[0046]

Embedded image

In the above definition, the term “compound residue containing one or more magnetically equivalent trifluoromethyl groups bonded to a carbon atom to which a hydrogen atom is not bonded” defined by R ^f is used in the wording thereof. As described above, a compound residue containing one or more trifluoromethyl groups, all the trifluoromethyl groups are magnetically equivalent, and all the trifluoromethyl groups are bonded to carbon atoms to which no hydrogen atom is bonded. There is no particular limitation as long as it is one. In particular,

[0048]

Embedded image

(Where k represents an integer of 1 to 5, and m represents 1
Or 2 is represented. R is

[0050]

Embedded image

Where A is

[0052]

Embedded image —CONH, —NH—, —NHCO—, —N
HSO _2- , -O-, -S-, -N- or -CON-

Represents However, when m represents 1, A is

[0054]

-CONH, -NH-, -NHCO-, -N
HSO _2- , -O- or -S-

When m represents 2, A is

[0056]

-N- or -CON-

Represents Also R

[0058]

Embedded image —C (CF ₃ ) ₃

In the expression, A is

[0060]

Embedded image

Represents the following. ),

[0062]

Embedded image —CH _p (CH ₂ OR) _3-p

(In the formula, p represents 0 or 1, and R has the same meaning as described above.)

[0064]

Embedded image-(CH ₂ ) _k CH _q (CONHR ¹ ) _3-q

(In the formula, k represents the same meaning as described above, and q represents 0 or 1. R ¹ represents

[0066]

Embedded image

Represents the following. )). First,

[0068]

Embedded image R ^f = − (CH ₂ ) _k AR _m , —CH _p (C
_{H 2 OR) 3-p,} - (CH 2) k CH q (CONH
R ¹ ) _3-q

Specific examples of the substituent in the case of the formula (I) are shown below, and R ^c corresponding thereto is shown to show specific examples of the preferred compound represented by the above general formula (I).

[0070]

Embedded image

For these R ^f , R ^c is [O-β-
D-galactopyranosyl- (1 → 4)]-D-gluconic acid, [O-β-D-glucopyranosyl- (1 → 4)]-
Compounds that are D-gluconic acid, D-galactonic acid, and D-mannonic acid residues are specific examples of preferred compounds represented by the above general formula (I).

[0072]

Embedded image

For these R ^f , R ^c is [O-β-
D-galactopyranosyl- (1 → 4)]-D-gluconic acid, [O-β-D-glucopyranosyl- (1 → 4)]-
Compounds that are D-gluconic acid, D-galactonic acid, and D-mannonic acid residues are specific examples of preferred compounds represented by the above general formula (I).

[0074]

Embedded image

For these R ^f , R ^c is [O-β-
D-galactopyranosyl- (1 → 4)]-D-gluconic acid, [O-β-D-glucopyranosyl- (1 → 4)]-
Compounds that are D-gluconic acid, D-galactonic acid, and D-mannonic acid residues are specific examples of preferred compounds represented by the above general formula (I).

[0076]

Embedded image

With ^respect to these R ^f , R ^c is [O-β-
D-galactopyranosyl- (1 → 4)]-D-gluconic acid, [O-β-D-glucopyranosyl- (1 → 4)]-
Compounds that are D-gluconic acid, D-galactonic acid, and D-mannonic acid residues are specific examples of preferred compounds represented by the above general formula (I).

[0078]

Embedded image

For these R ^f , R ^c is [O-β-
D-galactopyranosyl- (1 → 4)]-D-gluconic acid, [O-β-D-glucopyranosyl- (1 → 4)]-
Compounds that are D-gluconic acid, D-galactonic acid, and D-mannonic acid residues are specific examples of preferred compounds represented by the above general formula (I).

[0080]

Embedded image

For these R ^f , R ^c is [O-β-
D-galactopyranosyl- (1 → 4)]-D-gluconic acid, [O-β-D-glucopyranosyl- (1 → 4)]-
Compounds that are D-gluconic acid, D-galactonic acid, and D-mannonic acid residues are specific examples of preferred compounds represented by the above general formula (I). Next, the production method of the compound of the present invention will be described. The compound represented by the general formula (I) is, for example, a sugar lactone compound represented by the general formula (XI) (hereinafter abbreviated as “compound (XI)”).
And a fluorinated amino compound represented by the general formula (XII) (hereinafter abbreviated as “compound (XII)”). Scheme 1 shows the compound (XI) and the compound (XI
The reaction of I) was exemplified.

[0082]

Embedded image

(In the formula, R ^f and n have the same meanings as described above.) There are some compounds (XI) which are commercially available. However, from the corresponding commercially available saccharides, for example, under alkaline conditions, bromine, iodine, etc. Can be produced by a usual method of dehydrating a sugar acid obtained by oxidation. This dehydration reaction can be performed by a simple operation such as adding alcohol such as methanol or ethanol to sugar acid and repeating distillation under reduced pressure. However, even if the conversion to lactone is incomplete and some sugar acid remains, the above-mentioned condensation reaction is carried out. There is no problem. In the condensation reaction between compound (XI) and compound (XII), for example, an acid is converted into methanol, ethanol,
In an appropriate solvent such as an alcoholic solvent such as ethylene glycol, dimethylformamide, or an aprotic polar solvent such as dimethyl sulfoxide, at -50 ° C to 200 ° C,
Preferably at room temperature to 150 ° C, optionally with NaC
It can be produced by reacting in the presence of a suitable catalyst such as N for 10 minutes to 120 hours, preferably 1 hour to 10 hours. In the case of an amine having low reactivity, the reaction under high pressure (Ba)
ll. Soc. Chem. Jpn. , 62 , 3138
(1989)). Among the compounds (XII),
For example

[0084]

Embedded image

Although the following products are commercially available, the following fluorinated amino compounds are novel compounds and can be produced as follows.

[0086]

Embedded image (1) When R ^f = − (CH ₂ ) _k AR _m

1) When m = 1 A is

[0088]

Embedded image

Can be produced, for example, according to Scheme 2.

[0090]

Embedded image

(Wherein R and k have the same meanings as described above).

[0092]

Embedded image H ₂ NR

And

[0094]

Embedded image

After conversion to an acid chloride in the presence of a suitable condensing agent such as methylene chloride, tetrahydrofuran, diethyl ether, pyridine,
The reaction is carried out in the presence of a suitable base such as -N, N-dimethylpyridine, triethylamine or using the amine itself as a base, and the compound is reacted with the corresponding compound represented by the general formula (XIV) (hereinafter abbreviated as "compound (XIV)") ) Can be manufactured. In the case of acid chloride, Schotten-Baumann
Laws are also available. The reaction temperature is from -50 ° C to 200
° C, preferably from 0 ° C to room temperature, and the reaction time is from 10 minutes to 1 hour.
20 hours, preferably 30 minutes to 5 hours. Next, the phthalimide group of the compound (XIV) is converted into an amino group by hydrolysis using an acid or a base or by reaction using hydrazine, whereby the desired amine represented by the general formula (XV) can be produced. A is

[0096]

Embedded image

The amine can be produced, for example, according to Scheme 3.

[0098]

Embedded image

(Wherein, R and k have the same meanings as described above;
Ts represents a tosyl group. That is, first, a commercially available product [B] or a tosylate [C] easily derivable from the corresponding alcohol and the above amine

[0100]

Embedded image H ₂ NR

Is subjected to the usual conditions for alkylation of an amine to give compound (XVI). Then, the compound (XV
The reaction of converting the phthalimide group into an amino group described above from I) can produce the desired amine represented by the formula (XVII). A is

[0102]

Embedded image

The amine can be produced, for example, according to Scheme 4.

[0104]

Embedded image

(Wherein, R and k have the same meanings as described above).

[0106]

Embedded image RCOCl or RSO ₂ Cl

To synthesize amides [E] and [F], respectively. At this time, the usual Schotten
It is convenient to use the Baumann method. Then
The obtained [E] or [F] is reacted with potassium phthalimide in a suitable solvent such as dimethylformamide (DMF) or tetrahydrofuran (THF) to produce a compound (XVIII) corresponding to each A. From these, the phthalimide group is converted into an amino group in the same manner as described above, and the amine compound (XIX) corresponding to each A is converted.
Can be manufactured. The conversion from the bromo form [E] or [F] is carried out not by the method involving the imide form (XVIII) but by a method for synthesizing another primary amine, for example, the Deline method using hexamethylenetetramine,

[0108]

Embedded image NaN (CHO) ₂

A method using a method such as Compound (XX) in which A is an oxygen atom or a sulfur atom can be produced, for example, according to Scheme 5.

[0110]

Embedded image

(Wherein R and k have the same meanings as described above;
Ts represents a tosyl group. That is, for example, a commercially available bromo compound [H]
Alternatively, commercially available products of the tosylate [J] derived from the alcohol [G] can be obtained from 3-trifluoromethylphenol, 3,5-bis (trifluoromethyl) phenol, 3,5-bis (trifluoromethyl). )
The compound (XVIII) in which A represents an oxygen atom can be produced by subjecting the compound to a general Williamson reaction of reacting with an alkoxide (phenoxide) of an alcohol such as benzyl alcohol or perfluoro-t-butyl alcohol.
The compound (XVIII) in which A represents an oxygen atom can be obtained directly from the alcohol [G], for example, by using a commercially available 3,5
It can also be produced by a method in which a halide such as -bis (trifluoromethyl) benzyl chloride acts similarly. Further, if R is

[0112]

Embedded image

In this case, the compound (XVIII) can also be produced from the alcohol [G] by subjecting it to the conditions of Mitsunobu reaction. [H] or [J] is converted to a thiol such as 3-trifluoromethylthiophenol or 3,5-bis (trifluoromethyl) thiophenol in the presence of a suitable base such as sodium hydride or sodium methoxide in DMF, THF, or methanol. The compound (XVIII) in which A represents a sulfur atom can be produced by reacting in an appropriate solvent. From these imides, a phthalimide group is converted into an amino group in the same manner as described above, and each of the desired compounds (XX) can be produced. 2) When m = 2 A compound in which A represents a nitrogen atom can be produced, for example, according to Scheme 6.

[0114]

Embedded image

(Wherein, R and k have the same meanings as described above).
It reacts easily with benzyl chloride such as 5-bis (trifluoromethyl) benzyl chloride in the presence of a base to give compound [L]. [L] is subjected to the same reaction as in the above-mentioned scheme 5 to produce an imide (XXI) in which A represents a nitrogen atom. This compound (XXI) can be prepared from a commercially available secondary amine [M], for example, 3,3 ', 5,5'-tetrakis (trifluoromethyl) -dibenzylamine, compound [H] or [J And alkylation route. From the compound (XXI), which is a tertiary amine, the amino group is regenerated from the phthalimide group in the same manner as described above to produce the amine in which A represents a nitrogen atom. Further, a carboxylic acid [A] is reacted with a secondary amine [M] in the same manner as in the scheme 2 above,

[0116]

Embedded image A = CON

Compound (XXIII) can be prepared. From now on, similarly, the amino group will be regenerated and the desired compound (XX
IV) can be manufactured.

[0118]

(2) When R ^f = —CH _p (CH ₂ OR) _3-p

1) When p = 0 For example, it can be produced according to the route of Scheme 7.

[0120]

Embedded image Scheme 7

(Wherein, R has the same meaning as described above.) That is, an ether compound [N] can be produced from commercially available tris (hydroxymethyl) nitromethane by the same etherification method as in the above-mentioned scheme 5. The desired amine can be produced by regenerating the amino group from [N] in the same manner as described above. 2) When p = 1 For example, it can be produced by the route of Scheme 8.

[0122]

Embedded image

(Wherein, R has the same meaning as described above.) That is, first, commercially available epichlorohydrin is added to 3,5-bis (trifluoromethyl) phenol and 3,5-bis (trifluoromethyl) benzyl alcohol. , 3,
An alkoxide (phenoxide) such as 3 ', 5,5'-tetrakis (trifluoromethyl) benzohydrol or perfluoro-t-butyl alcohol acts to produce a diether compound [O]. If the amino group is regenerated from [O] by a conventional method, the desired amine can be produced.

[0124]

(3) R ^f = − (CH ₂ ) _k CH _q (CON
HR ¹ ) For _3-q

For example, it can be produced by the route of Scheme 9.

[0126]

Embedded image

(In the formula, R, k and q have the same meanings as described above, and Et represents an ethyl group.) That is, a commercially available ester [P] (q =
0, triethoxycarbonylmethane; q = 1, diethyl malonate) and the compound [H] or [J] described above.
The compound [Q] can be produced by alkylation using a conventional method. [Q]

[0128]

Embedded image H ₂ NR

At the same time, while distilling off the produced ethanol, the temperature is from 50 ° C. to 300 ° C., preferably from 100 ° C.
Reaction in a suitable solvent at ℃ or without solvent,
Alternatively, the amide compound (XXVII) can be produced by reacting in the presence of a suitable base such as sodium methoxide or sodium hydride. From this compound (XXVII), the desired amine can be produced by regenerating the amino group as described above.

When the compound of the present invention is used as an MRI contrast agent, a method for parenteral administration such as intravenous administration is usually used, but it can also be administered orally. Preparations for parenteral administration, that is, solvents or suspending agents used in the production of injections and the like include, for example, water, propylene glycol,
Examples include polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like. Preparation of the preparation may be performed by a conventional method. For oral administration, alone or in combination with a pharmaceutically acceptable carrier, for example, granules, fine granules, powders, tablets, hard syrups, soft capsules, syrups, emulsions, suspensions, liposomes Orally in the form of a liquid or the like. Examples of excipients used in producing a solid preparation include lactose, sucrose, starch, talc,
Examples include cellulose, dextrin, kaolin, calcium carbonate and the like. Liquid preparations for oral administration, ie emulsions, syrups, suspensions, solutions and the like, contain commonly used inert diluents, such as vegetable oils. The preparation may also contain, in addition to the inert diluent, auxiliary substances such as wetting agents, suspending aids, sweetening agents, flavoring agents, coloring agents or preservatives. Liquid preparations may be included in capsules of absorbable substances such as gelatin.

The MRI contrast agent according to the present invention is generally administered at a dose that allows the desired contrast effect to be obtained without side effects. The specific value should be determined at the discretion of the physician, but is generally 0.1 per adult per diagnosis.
It is 1 mg to 10 g, preferably 1 mg to 5 g. The compound of the present invention may be administered as an active ingredient in an amount of 1 mg to 5 g, more preferably 3 mg to 3 g per adult per one diagnosis. Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited to the following without departing from the gist thereof.

[0132]

【Example】

 Reference Example 1

[0133]

Embedded image

While stirring an aqueous solution (5 ml) of 2.0 g (10 mmol) of the amine salt on an ice water bath, the acid chloride 1.
64 ml (9 mmol) and a 2N aqueous sodium hydroxide solution were simultaneously added dropwise. The resulting solid was filtered, washed with water, and dried to obtain 3.6 g (quantitative) of the target amide. mp. 98-99 ° C IR (KBr) cm ⁻¹ 3326, 3100, 164
7, 1616, 1560, 1278 ¹ H-NMR (CDCl ₃ , 300 MHz) δ 3.6
3 (t, J = 5.9 Hz, 2H), 3.92 (dt, J
= 5.7, 5.9 Hz, 2H), 6.67 (bs, 1
H), 8.03 (s, 1H), 8.23 (s, 2H)

[0135]

Embedded image

To a solution of 3.5 g (9.5 mmol) of the bromide in dimethylformamide (DMF, 25 ml) was added 1.9 g (10.5 mmol) of potassium phthalimide.
The mixture was stirred for 7 hours on a 20 ° C. oil bath. Ice water was added to the reaction mixture, and the resulting solid was filtered, washed with water, and dried.
The obtained crude crystals were washed with ethyl ether to give 2.7 g (66%) of the desired imide. mp. 153-155 ° C IR (KBr) cm ⁻¹ 3302, 3088, 177
9, 1723, 1647, 1395, 1277 ¹ H-NMR (CDCl ₃ , 300 MHz) δ 3.7
8 (m, 2H), 4.05 (m, 2H), 7.16 (b
s, 1H), 7.75 (m, 2H), 7.88 (m, 2
H), 8.00 (s, 1H), 8.24 (s, 2H)

[0137]

Embedded image

A mixture of 2.6 g (6.1 mmol) of the imide, 320 mg (6.4 mmol) of hydrazine hydrate, and methanol (35 ml) was heated under reflux overnight. After distilling off methanol with a rotary evaporator, dilute sodium hydroxide was added and stirred. This mixture was extracted with ethyl ether, and the ether layer was washed with water and dried (MgSO 4).
O ₄ ), the target amine 1.9 by filtration and concentration
g (quantitative) was obtained. mp. 60-64 ° C IR (KBr) cm ^-1 3299,3092,294
6,1653,1620,1555,1383,128
_{^{1 1 H-NMR (CDCl 3}} , 300MHz) δ 3.0
0 (t, J = 5.8 Hz, 2H), 3.54 (dt, J
= 5.6, 5.8 Hz, 2H), 6.96 (bs, 1
H), 8.00 (s, 1H), 8.25 (s, 2H)

[0139]

Embedded image

960 mg (2.8 mmol) of lactone and 850 mg (2.8 mmol) of amine were added to methanol (7 mg).
ml) The solution was heated to reflux overnight. The residue obtained by concentrating the reaction mixture is subjected to ODS column chromatography (developing solution M
OH: water = 5: 2) to give the desired sugar amide 51
6 mg (29%) were obtained. mp. 121-123 ° C IR (KBr) cm ⁻¹ 3384, 2938, 165
3,1545,1381,1283,1136 ¹³ C-NMR (DMSO-d ₆ , 125 MHz) δ 3
7.91 (t), 39.5 (t), 60.3 (t), 6
2.3 (t), 68.2 (d), 70.5 (d), 7
1.1 (d), 71.4 (d), 72.1 (d), 7
3.2 (d), 75.7 (d), 82.9 (d), 10
4.6 (d), 123.1 (q, ¹ J (C, F) = 27
2.9 Hz), 124.7 (d), 128.0 (d),
130.4 (q, ² J (C, F) = 32.7 Hz), 1
36.7 (s), 163.5 (s), 172.8 (s) ¹⁹ F-NMR (DMSO-d ₆ , 282 MHz) δ −
61.6 (s) Example 4

[0141]

Embedded image

The reaction was carried out in the same manner as in Example 3 from 1.06 g (3.1 mmol) of lactone and 800 mg (3.3 mmol) of the amine, followed by ODS column chromatography purification (developing solution Me).
OH: H ₂ O = 3: 1) 1.2 g of the desired sugar amide
(66%). mp. 175-176 ° C IR (KBr) cm ⁻¹ 3395,2914,165
5,1541,1383,1352,1282 ¹³ C-NMR (DMSO-d ₆ , 125 MHz) δ 4
1.1 (t), 60.2 (t), 62.3 (t), 6
8.0 (d), 70.9 (d), 71.2 (d), 7
1.4 (d), 71.9 (d), 73.2 (d), 7
5.6 (d), 83.6 (d), 104.8 (d), 1
20.2 (d), 123.4 (q, ¹ J (C, F) = 2
72.9 Hz), 127.8 (d), 130.0 (q,
² J (C, F) = 32.7 Hz), 143.4 (s),
173.1 (s). ¹⁹ F-NMR (DMSO-d ₆ , 282 MHz) δ −
60.9 (s) Example 5

[0143]

Embedded image

2.3 g (10 mmol) of imidocarboxylic acid
l) was dissolved in 20 ml of pyridine, and 0.8 ml of methanesulfonyl chloride (10 m
mol) was added dropwise. After 30 minutes, 1.56 ml (10 mmol) of 3,5-bis (trifluoro) aniline was added, and stirring was continued for another 3 hours. The reaction mixture was poured into ice water, and the resulting crystals were filtered, washed with water, and dried. Recrystallized from methanol to give 2.97 g of the desired amide
(71%) as needles.

Mp. 268-269 ° C IR (KBr) cm ^-1 3330,3137,177
9,1732,1688,1632,1581,147
_{^{5,1422,1383,1273 1 H-NMR (CDCl 3}} , 300MHz) δ 4.5
6 (s, 1H), 7.62 (s, 1H), 7.80
(M, 2H), 7.93 (m, 2H), 7.99 (b
s, 1H), 8.02 (s, 2H) Example 6

[0146]

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2.85 g (6.85 mmol) of imide compound
Hydrazine monohydrate (0.38 ml, 7.5 mmol) was added to a mixture of hexane and methanol (50 ml), and the mixture was heated under reflux for 5 hours. After cooling to room temperature, methanol was distilled off using a rotary evaporator, and 1N NaOH 10 ml was added to the residue.
And 20 ml of water, and the mixture was vigorously stirred under a nitrogen atmosphere. After 30 minutes, the crystals were filtered and washed well with water. After drying, 1.58 g (80%) of the desired amine was obtained.

Mp. 96-97 ° C IR (KBr) cm ⁻¹ 3405, 3353, 322
9,3090,3000,1692,1584,147
_{^{4,1391,1277 1 H-NMR (CDCl 3}} , 300MHz) δ 1.6
8 (bs, 2H), 3.53 (s, 2H), 7.60
(S, 1H), 8.13 (s, 2H), 9.84 (b
s, 1H) Example 7

[0149]

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1.7 g (5.0 mmol) of lactone and 1.3 g (4.5 mmol) of amine were added to 22 ml of methanol.
And heated to reflux overnight. After cooling to room temperature, the generated solid was separated by filtration and washed with methanol to obtain 1.68 g (59%) of the target sugar amide. mp. 248 to 249 ° C. (decomp.) IR (KBr) cm ⁻¹ 3393, 3080, 294
8, 1684, 1657, 1552, 1385, 129
2 ¹³ C-NMR (DMSO-d ₆ , 75 MHz) δ 4
2.7 (t), 60.6 (t), 62.3 (t), 6
8.2 (d), 70.7 (d), 71.1 (d), 7
1.4 (d), 72.3 (d), 73.3 (d), 7
5.7 (d), 82.6 (d), 104.5 (d), 1
16.2 (d), 118.9 (d), 123.2 (q,
¹ J (C, F) = 272.5 Hz), 130.8 (q,
² J (C, F) = 32.5 Hz), 140.6 (s),
168.8 (s), 173.0 (s) ¹⁹ F-NMR (DMSO-d ₆ , 282 MHz) δ −
61.4 (s) Example 8

[0151]

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To a solution of 1.37 g (3 mmol) of the amine in pyridine (4 ml) was added 740 mg (3.3 mmol) of an acid chloride while stirring on an ice-water bath. After stirring overnight at room temperature, ice water was added. This was extracted with ethyl ether, and the ether layer was washed successively with dilute hydrochloric acid and water,
The residue obtained by drying (MgSO ₄ ), filtering and concentrating
Purification by _two column chromatography (developing solution n-hexane: ethyl acetate = 6: 1), 1.0 g of the desired imide compound
(52%).

Mp. 203-205 ° C IR (KBr) cm ⁻¹ 3428, 3297, 173
2,1669,1549,1422,1375,128
3,1178 ¹ H-NMR (CDCl ₃ , 300 MHz) δ 4.4
6 (s, 2H), 6.48 (d, J = 7.8 Hz, 1
H), 6.67 (bd, J = 7.8 Hz, 1H), 7.
69 (s, 4H), 7.77 (m, 2H), 7.88
(S, 2H), 7.90 (m, 2H) Example 9

[0154]

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From 830 mg (1.3 mmol) of the imide compound, 590 mg of the desired amine was obtained in the same manner as in Example 6.
(89%). mp. 127-128 ° C IR (KBr) cm ⁻¹ 3430, 3264, 165
5,1505,1372,1281 ¹ H-NMR (CDCl ₃ , 300 MHz) δ 3.5
0 (s, 2H), 6.53 (d, J = 8.6 Hz, 1
H), 7.67 (s, 4H), 7.88 (s, 2H),
8.29 (bd, J = 8.6 Hz, 1H)

[0156]

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Amine 510 mg (1 mmol), lacto
440 mg (1.3 mmol) in the same manner as in Example 3.
After the reaction, ODS column chromatography purification (developing solution MeO
H: H _TwoO = 3: 1) 400 mg of the desired sugar amide
(47%). mp. 155-157 ° C IR (KBr) cm^-1 3378, 2944, 283
0, 1624, 1464, 1360, 1281¹³ C-NMR (DMSO-d₆, 125 MHz) δ 3
7.9 (t), 60.6 (t), 62.3 (t), 6
8.2 (d), 70.5 (d), 71.1 (d), 7
1.4 (d), 72.1 (d), 73.2 (d), 7
5.7 (d), 82.9 (d), 104.6 (d), 1
23.1 (q,¹J (C, F) = 272.9 Hz), 1
24.7 (s), 128.0 (s), 130.4 (q,
^TwoJ (C, F) = 32.7 Hz), 136.7 (s),
163.5 (s), 172.8¹⁹ F-NMR (DMSO-d₆, 282 MHz) δ −
60.9 (s) Example 11

[0158]

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1.9 g (10 mmol) of the amide, 2.3 g (10 mmol) of phenol and 2.6 g (10 mmol) of triphenylphosphine were added to tetrahydrofuran 3
The mixture was dissolved in 0 ml, and 1.57 ml (10 mmol) of diethyl azocarboxylate was gradually added dropwise with stirring. After leaving overnight at room temperature, ether was added to the residue obtained by concentration, and the insoluble portion was filtered off. The residue obtained by concentrating the filtrate is subjected to SiO ₂ column chromatography (developing solution n-hexane: ethyl acetate = 4: 1 → 3: 1), and further recrystallized from ether / n-hexane. 2.1 g (52%) of an ether compound was obtained.

Mp. 114-116 ° C IR (KBr) cm ⁻¹ 3430, 1780, 171
7, 1614, 1395, 1360, 1285, 118
2,1115 ¹ H-NMR (CDCl ₃ , 300 MHz) δ 4.1
6 (t, J = 5.6 Hz, 2H), 4.32 (t, J =
5.6 Hz, 2H), 7.26 (s, 2H), 7.29
(S, 1H), 7.75 (m, 2H), 7.88 (m,
2H) Example 12

[0161]

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From 2.0 g (5 mmol) of the imide compound, 1.3 g (96%) of the desired amine was obtained in the same manner as in Example 2.
I got Oil IR (neat) 3304, 2943, 1614, 1
463, 1366, 1279 ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.4
1 (bs, 1H), 3.14 (t, J = 5.2 Hz, 2
H), 4.08 (t, J = 5.2 Hz, 2H), 7.3
2 (s, 2H), 7.46 (s, 1H)

[0163]

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From 1.3 g (3.7 mmol) of lactone and 1.0 g (3.7 mmol) of amine, 1.7 g (76%) of the desired sugar amide was obtained in the same manner as in Example 7. mp. 216.5-217.5 ° C. IR (KBr) cm ⁻¹ 3382, 1649, 161
5,1539,1463,1383,1360 ¹³ C-NMR (DMSO-d ₆ , 125 MHz) δ 3
7.3 (t), 60.6 (t), 62.2 (t), 6
7.2 (t), 68.1 (d), 70.3 (d), 7
1.0 (d), 71.3 (d), 72.1 (d), 7
3.2 (d), 75.6 (d), 82.6 (d), 10
4.5 (d), 113.7 (d), 115.6 (d),
123.1 (q, ¹ J (C, F) = 272.9 Hz),
131.5 (q, ² J (C, H) = 32.7 Hz), 1
59.3 (s), 172.7 (s) ¹⁹ F-NMR (DMSO-d ₆ , 282 MHz) δ −
61.0 (s) Reference Example 2

[0165]

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Ethanolamine 305 mg (5 mmol
l), 2.6 g (10 mmol) of benzyl chloride, 1.4 ml (10 mmol) of triethylamine in THF (5 m
l) The solution was heated to reflux overnight. After evaporating the solvent with a rotary evaporator, water was added to the residue, and the mixture was extracted with ethyl ether. Washing and drying of the ether layer (MgS
O ₄ ) and the residue obtained by concentration were subjected to SiO ₂ column chromatography (developing solution n-hexanal: EtOAc = 3:
1.84 g of the target dibenzylamine
(72%).

IR (neat) cm ^-1 3389,29
48, 2834, 1359, 1281 ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.8
0 (bt, J = 5.5 Hz, 1H), 2.79 (t, J
= 5.4 Hz, 2H), 3.77 (dt, J = 5.4,
5.5 Hz, 2H), 3.81 (s, 4H), 7.76
(S, 6H) Example 14

[0168]

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1.74 g of alcohol (3.4 mmol)
713 mg of p-toluenesulfonyl chloride (3.
75 mmol) was added. Furthermore, after stirring was continued at room temperature for 2 hours, water was added, and the mixture was extracted with ethyl ether. The ether layer was washed successively with dilute hydrochloric acid and water, and dried (M
gSO ₄ ), filtered, concentrated and crude tosylate (1.96)
g) was obtained. This was dissolved in DMF (10 ml), and 945 mg (5.1 mmol) of potassium phthalimide was added.
The mixture was stirred all day and night on a 110 ° C. oil bath. Ice water was added, and the formed solid was separated by filtration, washed (water), and dried. This was dissolved again in ethyl ether and treated with activated carbon. The obtained crude crystals were recrystallized from ethanol to obtain 1.30 g of the desired imide.
(60%).

Mp. 115-117 ° C IR (KBr) cm ⁻¹ 1771, 1715, 139
7, 1370, 1281, 1171, 1138 ¹ H-NMR (CDCl ₃ , 300 MHz) δ 2.9
0 (t, J = 6.0 Hz, 2H), 3.72 (s, 4
H), 3.88 (t, J = 6.0 Hz, 2H), 7.6
3 (s, 4H), 7.65 (s, 2H), 7.75
(M, 2H), 7.81 (m, 2H) Example 15

[0171]

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1.25 g of the imide compound (1.95 mmol)
l), hydrazine hydrate 100 mg (2.0 mmol
l), a mixture of methanol (12 ml) was heated to reflux overnight. After distilling off methanol with a rotary evaporator, dilute sodium hydroxide was added and stirred. The mixture was extracted with ethyl ether, and the ether layer was washed with water, dried (MgSO ₄ ), filtered and concentrated to obtain 950 mg (95%) of the target amine. Oil

IR (neat) cm ^-1 3412,29
36,1661,1537,1377,1283 ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.3
0 (bs, 2H), 2.64 (t, J = 6.2 Hz, 2
H), 2.87 (t, J = 6.2 Hz, 2H), 3.7
4 (s, 4H), 7.76 (s, 2H), 7.77
(S, 4H) Example 16

[0174]

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The reaction was carried out in the same manner as in Reference Example 3 from 620 mg (1.8 mmol) of the lactone and 930 mg (1.8 mmol) of the amine, followed by ODS column chromatography purification (developing solution: MeOH: H ₂ O = 5: 2). 1.05 g (68%) of the sugar amide was obtained. mp. 153-155 ° C IR (KBr) cm ^-1 3387,2938,164
7, 1545, 1379, 1290 ¹³ C-NMR (DMSO-d ₆ , 125 MHz) δ 3
6.5 (t), 54.8 (t), 57.4 (t), 6
0.6 (t), 62.4 (t), 68.2 (d), 7
0.6 (d), 71.2 (d), 71.4 (d), 7
2.1 (d), 73.3 (d), 75.7 (d), 8
2.9 (d), 104.6 (d), 120.3 (d),
123.4 (q, ¹ J (C, F) = 272.9 Hz),
129.0 (d), 130.0 (q, ² J (C, F) =
32.7 Hz), 143.4 (s), 172.4 (s) ¹⁹ F-NMR (DMSO-d ₆ , 282 MHz) δ −
61.3 (s) Example 17

[0176]

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2.54 g of imide alcohol (13.3 g)
mmol), 5.2 g of triphenylphosphine (19.
To a solution of 8 mmol) in 150 ml of tetrahydrofuran was added 3.12 ml (19.2 mmol) of diethyl azocarboxylate while stirring on an ice-water bath. After 5 minutes,
2.95 ml of perfluoro-t-butyl alcohol (2
1.2 mmol) was added. After the bath was removed and stirring was continued overnight, the solvent was distilled off. The residue was dissolved in a small amount, and the precipitated crystals were separated by filtration.
The residue was subjected to iO ₂ column chromatography (developing solution n-hexane: ethyl acetate = 8: 1 to 5: 1) to obtain 3.63 g (67%) of a target ether compound.

Mp. 75-76 ° C IR (KBr) cm ⁻¹ 1780, 1715, 161
6,1468,1431,1404,1252 ¹ H-NMR (CDCl ₃ , 300 MHz) δ 4.0
2 (t, J = 5.4 Hz, 2H), 4.28 (t, J =
5.4 Hz, 2H), 7.75 (m, 2H), 7.88
(M, 2H) Example 18

[0179]

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The reaction and post-treatment were carried out from 820 mg (2 mmol) of the imide compound in the same manner as in Example 15 to obtain 350 mg (63%) of the desired amino compound. Oil IR (neat) cm ^-1 2922, 1254 ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.4
5 (bs, 2H), 2.97 (t, J = 5.1 Hz, 2
H), 4.05 (bt, J = 5.1 Hz, 2H)

[0181]

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In the same manner as in Example 3, 340 mg (49%) of the desired sugar amide was obtained from 400 mg (1.2 mmol) of the lactone and 360 mg (1.0 mmol) of the amine. However, ODS column chromatography was performed with MeOH: H ₂ O = 3: 1. IR (KBr) cm ^-1 3409,2932,174
4,1657,1543,12713 ¹³ C-NMR (DMSO-d ₆ , 125 MHz) δ 3
8.0 (t), 60.5 (t), 62.3 (t), 6
8.2 (d), 68.4 (t), 70.3 (d), 7
1.1 (d), 71.3 (d), 72.0 (d), 7
3.2 (d), 75.7 (d), 79.3 (deca,
² J (C, F) = 30.2 Hz), 82.3 (d), 1
44.5 (d), 120.0 (q, ¹ J (C, F) = 2
93.0 Hz), 172.9 (s) ¹⁹ F-NMR (DMSO-d ₆ , 282 MHz) δ −
69.6 (s)

Example 20 Acute toxicity test 1 mg of the compound prepared in Examples 7 and 13 (hereinafter abbreviated as “Compound 7” and “Compound 13”, respectively)
/ Ml in physiological saline. This solution was administered to SD rats (male, 5-week-old body weight: 130-150 g, Charles River Japan) via a tail vein using a syringe at doses of 10, 20, and 30 mg / kg. Changes in body weight were measured daily, and changes in general condition were observed. Furthermore, on the 7th day, the animals were dissected, and changes due to drug administration were observed. No death of the treated animals was observed at all doses of Compound 7 and Compound 13. No abnormalities were observed in general symptoms, changes in body weight, and post-dissection examinations.

Example 21 Measurement of Distribution of Compound 13 into Main Organs Administered Intravenously to Rats Compound 13 was administered to rats in the same manner as in Example 20 for 30 m.
g / kg at 30 minutes and 60
After dissection, the liver, heart, lung, kidney, and spleen were collected one minute later. Each collected organ was shredded with scissors and 500
mg was weighed and homogenized with 3 ml of physiological saline.
To extract Compound 13 from the homogenized tissue dispersion, methanol (20 ml) was added, the mixture was vigorously shaken for 5 minutes, and then centrifuged (3000 rpm / min, 10 minutes) to collect the supernatant. . Further, the precipitate was redispersed in 30 ml of methanol, and the supernatant was collected by the same operation, and combined with the previously collected supernatant to obtain an extract.

In the extract,¹⁹F-NMR internal standard substance (constant
Perfluoro-t- produced in Example 17 as
0.1 mg / m of a butyl compound (hereinafter referred to as compound 17)
0.5 ml of 1 (0.24 μM) ethanol solution was added.
Thereafter, the mixture was concentrated using a rotary evaporator. Small amount in residue
Of ethanol, and the insoluble portion is filtered with a membrane filter.
It was filtered off. After concentrating the filtrate,¹⁹F-NMR spectrum
Compound 13: -62.8 ppm, Compound 17: -70.3
ppm (methanol-d_Four, Internal standard CFCl _Three))
The measurement was performed, and the amount of compound 13 in the organ was determined. As a result,
As shown in the table, an MRI diagnosis was performed on the liver, which is the target organ.
Is sufficient to selectively accumulate a sufficient amount of fluorine atoms.
It was recognized.

[0186]

[Table 1]

Example 22 Rat Liver Imaging with Compound 13 Urethane anesthetized Wistar rats (male, 5 weeks old, weighing 140 g) were administered with 3 mg / ml of compound 13 (20% DM).
(SO / saline) solution as in Example 20 (5
0 mg / kg), an F / H tunable surface coil was applied to the upper abdomen, and the proton nucleus and fluorine nucleus
Attempted imaging. The apparatus uses a 7 tesla horizontal bore MR system SIS300 / 183 manufactured by SISCO, with a proton nucleus at 300.061 MHz and a fluorine nucleus at 282.30.
Observed at 2 MHz. The pulse sequence is such that the proton nucleus has a spin echo method (T1-weighted), TR = 100 ms,
TE = 6 ms, number of integration = 32 times, slice thickness = 3 m
m, fluorine nuclei are one-dimensional chemical shift imaging (P
E1D), TE = 3 ms, and the number of integrations = 256 times. As a result, a fluorine nucleus spectrum was selectively obtained from a region considered to be liver in the T1-weighted image. That is, a fluorine nucleus spectrum is observed only in the liver region (black portion) of the T1-weighted image of the image shown in FIG. It was confirmed that.

[0188]

Industrial Applicability The compound of the present invention gives a strong singlet ¹⁹ F signal in MRI and has tissue selectivity, so that it is useful for clinical application of ¹⁹ F-MRI diagnosis. In addition, the compound of the present application, due to its structural features,
It is considered to be useful for application to ¹⁹ F-MRS (magnetic resonance spectroscopy).

[Brief description of the drawings]

FIG. 1 is a drawing showing an image of rat liver imaging using a compound of the present invention (compound 13).

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical indication location C07C 311/15 7419-4H C07C 311/15 323/25 7419-4H 323/25 C07H 3/00 C07H 3/00 5/02 5/02 5/06 5/06

Claims (13)

[Claims] 1. A following formula (I) ## STR1 R ^c NHR ^f (I) (wherein, R ^c represents a sugar chain acyl residues having tissue selectivity, R ^f is not bound hydrogen atoms carbon 1 attached to an atom
Or a compound residue containing a plurality of magnetically equivalent trifluoromethyl groups). 2. The fluorine-containing sugar derivative according to claim 1, wherein R ^c represents a sugar compound acyl residue represented by the following formula (II). Embedded image (Wherein, n represents an integer of 0 to 4) 3. The method according to claim 1, wherein R ^c is the following formula (III) or the following (IV):
The fluorine-containing sugar derivative according to claim 1, which is represented by the formula: Embedded image 4. The method according to claim 1, wherein R ^c is represented by the following formula (V):
The fluorine-containing sugar derivative according to claim 1, which is a β-D-galactopyranosyl- (1 → 4)]-D-gluconic acid residue. Embedded image 5. The method according to claim 5, wherein R ^c is represented by the following formula (VI):
The fluorine-containing sugar derivative according to claim 1, which is a β-D-glucopyranosyl- (1 → 4)]-D-gluconic acid residue. Embedded image 6. The fluorine-containing sugar derivative according to claim 1, wherein R ^c is a D-galactonic acid residue represented by the following formula (VII). Embedded image 7. R ^c is represented by the following (VIII) Formula D-
The fluorine-containing sugar derivative according to claim 1, which is a mannonic acid residue. Embedded image 8. The method according to claim 8, wherein R ^f is (In the formula, k represents an integer of 1 to 5, m represents 1 or 2. R represents Wherein A is -CONH, -NH-, -NHCO-, -N
Represents HSO ₂ —, —O—, —S—, —N— or —CON—. However, when m represents 1, A represents -CONH, -NH-, -NHCO-, -N
When m represents 2, A represents -N- or -CON- when HSO _2- , -O- or -S- is represented. Also, when R represents embedded image -C (CF _{3) 3,} A represents embedded image -O-. ), Embedded image _{-CH p (CH 2 OR) 3} -p ( wherein, p is 0 or 1, R represents the same meaning) or embedded image -. (CH _{2) k} CH _q (CONHR ¹ ) _3-q (wherein, k represents the same meaning as described above, and q represents 0 or 1. R ¹ represents Represents The fluorine-containing sugar derivative according to claim 1, wherein 9. An MRI contrast agent comprising the fluorinated sugar derivative according to claim 1 as an essential component. 10. A pharmaceutical composition for in-vivo diagnosis comprising the fluorine-containing sugar derivative according to claim 1 and a pharmaceutically acceptable carrier. 11. The following formula (IX): H ₂ NR ^{f1 wherein} R ^f1 is — (CH ₂ ) _k AR _m , —CH _p (CH ₂ O
R) _3-p or _{- (CH 2) k CH q} (CONHR 1)
_3-q (wherein, k, m, p, q, R, A and R ¹ have the same meanings as described above). ] The fluorinated amino compound represented by these. 12. The following formula (X): (Wherein, R ^f1 has the same meaning as described above.) 13. The following formula (XI): (Wherein n has the same meaning as described above) by converting the sugar lactone compound represented by the following formula (XII) to H ₂ NR ^f (XII) (where R ^f has the same meaning as described above) Wherein the reaction is carried out with a fluorinated amino compound represented by the following formula (XIII): (Wherein n and R ^f have the same meanings as described above).